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Journal of Psychoactive Drugs

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The Background and Chemistry of MDMA

Alexander T. Shulgin

1483 Shulgin Road, Lafayette , California , 94549

Published online: 20 Jan 2012.

To cite this article: Alexander T. Shulgin (1986) The Background and Chemistry of MDMA, Journal of Psychoactive Drugs,
18:4, 291-304, DOI: 10.1080/02791072.1986.10472361
To link to this article: http://dx.doi.org/10.1080/02791072.1986.10472361

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The Background and Chemistry

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ofMDMA

AL EXANDER T. SH ULGIN . PH.D . *

This article will present the factual material that

exists in the literature representin g the results of laboratory studi es and sc ie ntific e xpe rime ntati o n with
methylenedi oxymethamphetamine or MDMA, the common name applied to an organic compound, a secondary
amine. As a free base it is a white , musty smelling oil with
a searing taste , insoluble in water but soluble in most
organic solvents. It forms salts with several acids, and
these are white solids or oils that are readil y water soluble
and bitt er to the taste . It has an empirical formula
C llH 1sN02 , and its structural formula is given in Figure
I.
MDMA has a number of correct chemical names,
each based on one portion or another of the chemi cal
structure . With that defining portion named as a stem
word . the full chemical name is apparent by the additions
to this base fragment. In Figure I , the fragments (with
their names) are drawn on the left and the extended name
that applies to MDMA is given on the right. The use of the
simplest aliphatic chain (i.e . . ethylamine or isoprop ylamine) occ urs in part to avoid the generic name amphetamine or methamphet amine . These terms are so frequentl y
used that each listener conjures up an image of the chemicals being described . accordin g to his/her discipl ine: the
chemist sees the carbon chain, the pharmacol ogist sees the
stimulant. and the policeman sees the drug laws. The
names that are to be used in the searching of Chemical
Abstracts depend on the date of the search. In the earl iest
files. the homopiperonylamine name was used , and then

up to 1972, MDMA was entered with the phenethylamine

name . Since then, the heteroc yclic term benzodioxole-5ethan amine has been the root name . The common abbreviation MDMA is based on the consideration of the structure as a substituted methamphetamine. Other terms that
have been used to refer to this drug include MDM , Ecstasy, XTC , Adam , and EA-1475 (the last , by the Edgewood Arsenal) . The computer searching of Chemical
Abstracts employs the following registry numbers:
66142 -89-0
S-MDMA ( + )
69558 -32-3
S-MDMA ( + ) HCI.
R-MDMA (-)
81262-70-6
69558-31-2
R-MDMA ( -) HCI
MDMA (racemic)
69610-10-2
MDMA HCI (racemic)
64057 -70-1
CHEMISTRY

Synthesis
There are six method s of preparation to be found in
the scientific literature. In all cases, the starting material
carries the preformed methylenedioxy ring , in the form of
safrole, isosafrole, or of the derived aldehyde , piperonal .
The first preparation and description of MDMA was a
German patent issued to the firm E. Merck (1914) in
Darmstadt, dated December 24 , 1912, and made available May 16, 1914. Here, MDMA was synthesized in two
steps from safrole. The addition of aqueous hydrobromic
acid provides an impure intermediate ( 1methylenedioxyphenyl-2-bromopropane) that is converted with an alcoholic solution of methylamine to
MDMA . The same process , except for the isolation and

*1483 Shulgin Road. Lafayette. California 94549 .

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CHEMISTRY

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MDMA

FAMILY
Structure

CH7:
A.

CH2

MDMA NAME
Name
2-Methylamino-l-(3,~-methylene-

Propane

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dioxyphenyl)-propane

CH3
Isopropyl amine

N-Methyl-6-(3,~-methylenedioxy-

phenyl)-isopropylamine

Ethyl amine

N,a-Dimethyl-6-(3,4-methylenedioxyphenyl)-ethylamine

Phenethylamine

N,a-Dimethyl-3,4-methylenedioxyphenethylamine

Benzeneethanamine

N,a-Dimethyl-3,4-methylenedioxybenzeneethanamine

Amphetamine

N-Methyl-3,~-methylenedioxy-

amphetamine

Methamphetamine

3,~-Methylenedioxy-methamphetamine

Homopiperonylamine N,a-Dimethylhomopiperonylamine
Benzodioxole-Sethanamine

N,a-Dimethylbenzodioxole-Sethanamine

Figure 1. Chemical structures of MDMA and its fragments. with extended MDMA names.
Journal of

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CHEMISTRY

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SHULGIN

purification of the bromo intermediate, was described by

Polish chemists almost 50 years later (Biniecki &
Krajewski 1960).
MDMA has also been synthesized from MDA by
reaction with ethyl chloroformate , followed by reduction
with Red-AI (Davis & Borne 1984). Similarly, MDA can
be converted to the formam ide that is reduced with lithium
aluminum hydride in tetrahydrofuran (Braun, Shulgin &
Braun 1980a). One report (O'Brien, Bonicamp & Jones
1982) described the methylation of MDA with methyl
iodine . MDMA was obtained, but the dimethylated tertiary amine and the trimethylated quarternary products
were also generated as contaminants.
Two procedures exist for the synthesis of MDMA by
the reductive amination of piperonyl acetone with methylamine. The reducing agents are either sod ium cyanoborohydride in methanol (Braun , Shulgin & Braun 1980a) or
amalgamated aluminum in aqueous isopropanol (see
Nichols, in Frith 1986b). The cyanoborohydride method
has been used for the preparation of tritium-labeled
MDMA using labeled methylamine (Gehlert et al. 1985).
Piperonyl acetone may also be reacted with Nmethylformamide in the Leuckart reaction , and MDMA
obtained by the hydrolysis of the intermediate N-formyl
derivative (Bailey et al. 1975) . This N-formyl intermediate is also the topic of an early German patent describing
its formation from MDMA and chloral hydrate (Merck
1920) .
The piperonyl acetone required for these syntheses is
available commercially . (See comments below for labeling misidentifications.) It can also be made either by the
reduction of the nitroethane adduct of piperonyl with
elemental iron or the oxidation of isosafrol with hydrogen
peroxide in formic acid.

incorrect starting material would lead to 1-(3,4methylenedioxyphenyl)-3-aminobutane (HMDA) (Shulgin & Jacob 1982a, 1982b) . The structure for this alternate "piperonylacetone" is also given in Figure 2.
Onl y a modest pharmacological literature exists on
the se two aminated homologues . One study (Kasuya
1958) has compared HMDMA with atropine and found it
to be a weak spasmolytic. The toxicity and pharmacology
of this homologue in mice (and of the corresponding
MDA homologue HMDA) have been studied and published (Davis & Borne 1984) . The primary amine HMDA
was found to be inactive (in rats at 10 mg /kg) in both open
field testing and as a stimulant (Buxton 1972). but at
higher doses caused slight stimulation with tremors, and
modest inhibition of monoamine oxidase (Fellows &
Bernheim 1950) .

PHYSICAL PROPERTIES
OFMDMA
The free base has a boiling point in \'lieI/o of 155 at
20 mm /Hg (Me rc k 1914) and 110_120 at 0.4 mm /H g
(Braun. Shul gin & Braun 1980a) . The hydrochloride salt
can occur in a number of hydrated cry stalline forms.
making the physical properties and solid spectra of risky
value for identification and as criteria of purity . The
following melting points (rn .p.) are given : for anh ydrous.
147_148 (Bailey et al. 1975) . 148-149 (Biniccki &
Krajewski 1960). 148_150 (Davis & Borne 1984 : Merck
1914l.1500-151(Gaston&Rasmussen 1972).151 -152
(Braun. Shulgin & Braun 1980 a ). 152-153 (Braun .
Shulgin & Braun 1980a). 158-159 (Nichol s . In: Frith
1968b): for quarter-hydrate . so fte n 132 and m .p . 135
139 (Shulgin 1986) : for hemihydrate. soften 92 and
m . p. 138_145 (Shulgin 1986): for three-quarter hydrate.
soften 50 and m .p , 9(f-132 (Shulgin 1986) : for monohydrate. softe n 80 and m.p . )07 _133 (Shulgin 1986).
It is apparent that with uncertain hydration , the melting point is not an acceptable criterion of identity or of
purity . Each of these polymorphs has , however, a distinct
and characteristic crystalline polymorphic structure . The
index of refraction has been determined: n '6 = I. 5311
(Biniecki & Krajewski 1960).
A considerable body of spectral data exists for
MDMA. As mentioned above, the several polymorphs of
the hydrated hydrochloride salts have distinct infrared
spectra . Some of these are shown in Figure 3. The spectra
of the free base (Nichols, In : Frith 1986b; Bailey et al.
1975) and the anhydrous hydrochloride salt (Bailey et al.
1975; Gaston & Rasmussen 1972) have been published.
The latter are as KBr pellets, a spectral procedure that can
dehydrate a material during preparation .
The ultraviolet spectrum is characteristic of the

Synthetic Precautions
Some potential synthetic mishaps should be considered . Substitution of isosafrole for safro le leads. in the
reaction with hydrogen bromide. to an isomeric bromopropane intermed iate that on amination with ammonia
produces an a-aminated analogue of MDMA (Merck
1914) . Pre sumably. the sub stitution of the meth ylamine .
as in the procedure above. would produce 1-(3,4-methylenedioxyphenyl )-I-methylaminopropane. the benzyl amine isomer of MDMA.
In the syntheses starting with piperonylacetone , the
substitution of 1-(3,4-methylenedioxyphenyl)-3butanone for 1-(3,4-methylenedioxyphenyl)-2-propane
(an error that as been made by commercial suppliers of
piperonylacetone) leads to the formation of 1-(3,4me th y Ie ned i x ox yphe n y I) - 3 - me t hy Iami no bu tane
(HMDMA); with ammonia rather than methylamine, this
Journal

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SHULGIN

CHEMISTRY

-~

AR-CH=CHCH3

(Isosafrole)

AR-CHO
(Piperonal)

AR-CH2CH=CH2
/

(Safrole)

i~//

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~~/

Piperonylacetone

AR-CH2CCH3
II

o
(Piperonyl-)

AR-CH2CH2CCH3
II

(the "right" ketone)

(the "wrong" ketone)

Figure 2. Sy nthetic routes to MDM A.

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SHULGIN

.>
1_

.,
"

' l

:I

S- fO R'"

'

CHEMISTRY

lr)1l~r.~i 1~~Y

,j
" DIU HCl.

' )

I'
I

Figure 3. MDMA spectra.

Journa l of Psvchoactive Drugs

295

Vo l. IX(4) Oct-Dec. 19B6

CHEM ISTRY

SHULGIN

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Jour nal of Psvchoactive Drugs

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C HE MIST RY

SHULGIN

methylenedioxyphenyl ring (as the hydrochloride in ethanol , 286 nm , e = 3843 [Ba iley et al. 1975]; as the sulfate in
water, 0.1 N, 284 nm, A 1% I cm = 164 [Gaston &
Rasmussen 1972]). It is excellent for quantitative analysis, but is of little value for qualitative identification . The
nuclear magnetic resonance spectra have been published,
in part , both as the free base in CDCI 3 and as the HCI salt
in 0 20 by Bailey and colleagues (1975 ) and, in full , by
Nichols (In: Frith 1986b). Mass spectral data have also
been published (see Figure 4), both with electron impact
(Bai ley et al. 1975 ) and with che mica l ioni zation
(Nichols, In: Frith 1986b).

with locomotor activities (Harris 1985).

Rats
The study by Hardm an, Haavik and Seevers (197 3)
reported the LDso in rats to be 49 mg/kg i.p. Orally.
however, MDMA is less toxic , with an LD so in rats of325
rng/kg being reported (Goad 1985).
Guinea Pigs
The study by Hardman , Haavik and Seevers ( 1973)
reported an LD so in guinea pigs of 98 mg/kg i.p.
Dogs
In dogs, following intravenous injection , the LD so
was reported to be 14 rng/kg (Hardman, Haavik & Seevers
1973). The death of one dog was observed at an oral dose
of 18 rng/kg in toxicity trials preliminary to behavioral
studies (Frith 1986a ). In this latter study , however,
chroni c oral treatment of 15 rug/kg led to no further
death s.

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ANALYTICAL PROCEDURES
Chromatographic analytical schemes have been developed . Two thin-layer chromatographic reports have
appeared, one with six solvent systems (Bailey et al.
1975) and another with two, but with a progressive color
development technique (O' Brien, Bonicamp & Jones
1982). A third study (Shaw & Peel 1975) was erroneously
titled MOM A and actually investigated MMDA . Several
reports of gas chromatographic analy ses have been published , and this technique appears to be an excellent
measure of both identity and purity (Nichols, In: Frith
1986b; Gupta & Lundberg 1977; Bailey et al. 1975;
Gaston & Rasmussen 1972).

Monkeys
Intravenous admin istration of MDMA to monkey s
(Macaca mulatta) provided an LD so of 22 rng/kg (Hard man, Haav ik & Seevers 1973).
Several studies have been made of toxicolo gical
change s in chemistry or body condition of both rats and
dogs at sublethal levels of MDMA . Studies in subacutely
treated rats (subcutaneous admini strations twice daily for
four days at 10, 20 and 40 mg/kg ) led to exten sive decrease of hippocampal serotonin levels as seen in postmortem assays after a two-week wait. There was little
change in either norep inephrine or dopamine levels
(Woolverton et al. 1985). A single injection at the highest
level produced a similar depletion (76% rather than 88%,
relative to control animal s). A prelim inary report of these
finding s was submitted as evidence to the Drug Enforcement Administrat ion (DEA) hearings on MDMA (Seiden
1985), and it was a report of parallel finding s in the rat
following MDA admini stration (Ricaurte et al. 1985) that
was used to support the emergenc y scheduling ofMDMA .
Similar finding s were reported , as a preprint to the DEA
for use at the MDMA hearing s, by Schmidt, Wu and
Lovenberg (1985 ) and later publi shed as an abstract
(Schmidt & Lovenb erg 1986). The y too found that adm inistration of high acute dosages of MDMA in rats depleted
brain serotonin. The y also found that pretreatment of the
test animal with an antidepressant (citalopram) known to
block serotonin uptake mechani sms prevented this decrease in serotonin. These findings are in agreement with
studies of the levels of brain enzymes that are involved

TOXICOLOGY
The mean lethal dose (LDso) of MDMA has been
determ ined in several animal species . The first thorou gh
study of the toxicity and beha vioral pharmacology of
MDMA was conducted at the University of Michigan
during the period 1953-54, and was supported by a contract from the Army Chemical Center. The results were
decla ssified in 1969 and published four years later (Hardman , Haavik & Seever s 1973). In this study, a total
number of eight drug s were studied in five animal spec ies.
In all five spec ies examined in this study, MDMA proved
to be less toxic than MDA , but more toxic than mescal ine .
A number of other studies, often to determine beha vioral
respon ses or sublethal morb idity, have provided additional data . These are presented here by animal species .
Mice
The seminal study of Hardman , Haavik and Seevers
( 1973) determined the LD so of MDMA in mice to be 97
rug/kg following intraperitoneal (i . p. ) admini stration.
More recent studies by Davis and Borne (1984) provided
the same value (98 mg/kg i.p.) in isolated test animals.
Aggregate toxicity, however. was found to be considerably higher (20 mg/kg ), with a number of deaths being
delayed . Thi s latter value was also reported in conjunction
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with the formati on of neurotransmitters (Stone et al.

1986) . Tryptophan hydroxylase activity in rats treat ed
with MDA or MDMA (10 rug/kg subacutely) decreased
in certain brain area s, unlik e the decrease in tyro sine
hydrox ylase associated with high-lev el administration of
methamphetamine . Rats administered MDMA (or separately . MDA ) subac utely ( 10 mg/kg sub cutaneou sly) were
shown to have an incre ased neurotensinlike immunoreactivity level in certain region s of the brain (Merchant et al.
1986).
In a separate study (Goad 1985) of subacute ly treated
rats (oral admini strations daily in increasing increments of
25 mg/k g per day for 13 day s), survivors were sacrificed
for tissue and brain pathology studies after a three-week
wait. There were blood indicators of damage to both liver
and kidney , but histological studies of brain tissue revealed no path olo gy (Frith 1986b ).
Dogs administered MDMA on a chronic basis at oral
dosages of up to 15 mg/kg /day showed restricted weight
gain , and in several males at the highe st dosage s, testicular atrophy . Ob served possible central nervous sys tem
(CNS) lesion s were believed to be artifacts (Frith 1986a) .

of radio-labeled MDMA in rat brain homogenates ha

been reported (Gehlert et al. 1985) , and several drug
were evaluated as inhibitors of binding or as displacinj
agents . Studies observing neurotransmitter release in ra
brain striatal slices showed MDMA to have a potencj
similar to the neurotoxin para-chloroamphetamine in the
release of serotonin. Dopamine wa s found to be les:
affected (Levin, Schmidt & Lovenberg 1986). In general
these studies tend to imply some functional role of seroto nin in the mechanism of action of MDMA .
In vivo Studies
Studies have been conducted on both restrained
(electrodes, thermocouples) and freely moving animals
(drug discrimination , behavioral pharmacology). A
single report involved brain biochemistry with indwelling
electrodes (Takeda et al. 1986 ) measuring MDMAinduced efflux of neurotransmitters by voltammetry in
anesthetized rats . It was felt that the small amount of
dopamine release see n might be due to the changes seen in
serotonin level s.
An experimental procedure has been developed that
shows a remarkably good co rrelation between the qualitative nature of a drug -induced rise in a rabbit's temperature
(measured rectally) and the stimulant or psychotomimetic
character of the tested drug. The extent of this temperature
rise is proportional to the potency of the tested drug as a
psychoactive agent in humans (Aldous et al. 1974). This
assay, when applied in rabbits to the optical isomers of
MDA and MDMA , showed a reversal of potencies of the
isomers (Anderson et al. 1978). Thu s , with MDA the R
(levo-, 1-) isomer is more potent than either the S isomer or
the racemate, whereas the S (dextro- , d- ) isom er of
MDMA is the more potent. Thi s is true in rabbit studies
and in human evaluations as well. Thi s reversal of active
isomer assignment, coupled with the absence of cro sstolerance between MDMA and MDA in humans , supports
the hypothesis that these two drugs have different mechanism s of action .

PHARMACOLOGY
In vitro Studies
Studi es have been conducted using various in vitro
systems for the purp ose of eva luating the relationship
between MDMA and variou s neurotransmitters. Mo st
frequentl y . the neurotransmitt er serotonin has been the
focal point of these studies . Assaying the opti cal isomers
of MDMA (in rat brain synaptosomes ), Nichol s and col league s ( 1982) have found that the enantiorncr of MDMA
effective in humans (the S or + isomer) is the more
ef fective isom er in releasin g serotonin. The study of the
opti cal isom ers of MDMA on the inhibition of the uptake
not only of serotonin. but of other neurotransmitter s, is the
subject of a recently completed master of science thesis
(Stee le 1986), which has been publicly presented (Steele,
Nichols & Yim 1986 ). Studi es have been made to determine the affinit y of both MDA and MDMA for serotonin
and dopamin e receptors (Lyon , Glennon & Titeler 1986) .
Tritiated serotonin and ketanserin were used to label 5HT) and 5-HT 2 recept or s respectively, and the dopamine
receptors were labeled with N-mcth ylspip erone. All studies indicated a mod erat e affinity for the 5-HT 2 receptors ,
with less for the 5-HT ) and very much less for the dopa mine receptors. In all cases the R isomer was more effective than the S isom er , with the racemate being intermedi ate in effec tive ness. As the S isomer of MDMA is the
more effective in humans, it was felt that thes e findings
indica te a possible amph etamin e-associated mechanism ,
rather than ju st serotonin involvement. Specifi c bind ing
J ournal

( ~l

Ps vchoact ivc Drug

Drug Discrimination
A pharmacological technique that recently has been
quite popular as a tool for comparing psychoactive drugs
in experimental animals is the drug-discrimination assay .
In this assay , test animals are trained to discriminate
between a given active compound and (usually) saline.
Then the behavior seen resulting from varying dosages of
a trial drug allows some qualitative assignment of action .
Furthermore, two experimental drugs may be compared
one again st the other in order to determine their relative
quantitative ranking .
Studies with rats trained to discriminate between
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SH ULGI N

d-amph etamine and saline or, separately, between MDA

and saline, have shown MDM A in both cases to generalize to the drug in preference to the saline (Glennon &
Youn g 1984 ). Thi s , together with the finding s that
MDMA did not (unlike MDA) generalize to animals
tra in ed to d iscrim in at e 2, 5- di me thoxy-4- me thy lamphetamine (DOM) from saline (Glennon et al. 1982),
sugges ted th at N-m ethylat ion of MD A (to produce
MDMA) emp hasizes the stimulant properties in preference to the psychedelic propert ies. In separate studies,
howe ver , rat s tra ined to d iscrimin ate between damphetamine and saline, MDMA was found to only partially mimic d-amph etamine (Woo lverton et al. 1985). In
rhe sus mo nkeys train ed to discr im inate between damphetamine and saline, MDMA appeared to be amphet aminelike, whereas MDA showed only partial mimick ing
of d-a mphetamine (Woo lverton et al. (985).

and defecation . A picture of disorientation and fear was

presented for mescaline , and MDMA (in adequate doses)
was said to parallel this picture, but no explicit deta ils
were given . These effects were apparently not seen in the
monkey in this study. A similar study in the macaqu e
(Schlemmer, Montrell & Davis 1986) at doses of up to 10
mg/kg showed some disruption of social beha vior (i.e. ,
self-groo ming, food foraging), but no actions that suggested hallucinatory effects.
In rats, with orally adm inistered MDMA , there were
adverse clinical signs- largely relat ed to excitability
(i.e., piloerection , uncontrolled urination) -seen in all
studies at or above 25 mg/kg . At higher levels (to 300
mg/kg) there were tremors and convul sions observed ,
with death resulting above this dose (Frith 1986b; Goad
1985). In similar studies with dog s administered nearlethal levels of MOM A orally, toxic behav ioral signs were
observed, such as rapid breathing , salivation and hyperactivity (Frith 1986a).
Two studies were solicited by the federal government to evaluate the abuse potent ial of MDMA through
reinforcement studies (self-administration) in cocainetrained primates. The first of these employed pretrained
baboon s (Griffiths, Lamb & Brady 1985) and found that
two out of three animals reinforced them selve s with
MDMA , but with less intensity than with coca ine . The
third animal did not self-administer MDMA on initial
trials, but appeared to do so on retrial. A second study
(Harris 1985) employed rhesus monke ys, also pretrained
to self-administer coca ine. Again, some reinforcement
was found in two out of three animal s, suggesting a real
abuse potential for MDMA.

Behavioral Pharmacology
A number of studies were made of MDMA , in comparison to both the primary amine (MDA) and the higher
N-homologues, both as an analgesic and as a CNS stimulant in mice (Braun, Shulgin & Braun 1980a , 1980b).
MDMA proved to be the most effective analgesic of all
comp ound s tested , especially in the test that measures the
loss of stretch refle x as a response to injected acet ic acid .
MDMA , and the immediate N-ethyl homologue MOE ,
were the most effective com pound s in promoting motor
activity. In this assay, they had more than twice the
potency of MDA as stimulants.
Many of the observations on drug-induced behavioral changes are natural consequences of toxicity studies ,
and hence often reflect doses that approac h, and in some
cases exceed , the LD so levels. When near-lethal amount s
of MDMA are given to mice, the observed beha vior has
been described as being exc itatory in nature (tremors,
jerking, head clonus that progressed to clonic convulsions). Tonic seizures did not occur (Davis & Borne
1984). In discrim inative stimulus studies conducted in
rats (Glennon & Young 1984) doses in excess of 1.6-3.0
mg/kg could not be considered, due to behavior disruption
(i.e ., lack of any response at all). Hardm an, Haavik and
Seevers (1973) made behavioral observations of MDMA
in the dog and in the monkey at substantially lethal doses
(in the dog , between five and 50 rng/kg , with the
LDso = 14 mg/kg; in the monke y, between 10 and 75
mg/kg, with the LD so = 22 mg/kg). Under these conditions, a spectrum of behavior similar to that of mescaline
was observe d (mescaline dose range in the dog, five to 60
mg/kg, with the LD so = 54 mg/kg). This spect rum initially included motor effects (a weakness and a fluttering
motion in the hind limbs) followed by salivation, emesis
Journ al

or Psvchoacti vc Dru gs

PSYCHOPHARMACOLOGY

Nonclinical Studies
The earliest report s of human activity of MDMA
were from research studies that were not clinically
oriented. The first descripti on of its action in human s
(Shulgin & Nichols 1978) stated that it evoked an easi ly
controlled altered state of con sciou sness, with emotional
and sensual overtones. It shared a property with low levels
of MDA in that it had little hallucinatory effe ct. A subsequent report (Shulgin 1983) elaborated more on the quality of action .
Most of the known psychedel ic drugs suffer a major
loss of potency on N-methylation (Anderso n et al. 1978 ).
MDMA is the one exce ption to this rule as it, like amphetamine, maintains potency as the N-methyl homologue.
This pair is set apart also by the reversal of optica l isomer
configuration required for human activity, and the fact
that there is no observed cross-to lerance between MDA
and MDMA (Anderson et al. 1978).
2l)l)

Vo!. I X(4 ) Gel -Dec . I lJXfl

C HEM IST RY

SH ULGIN

From a larg e number of clinical trial s, it became

increasin gly appa rent that MDMA was with out the har shness and co mplex ity usually see n with MDA . Thi s,
co upled with the reversal of the optical isomer requirement for optimum hum an response , led to a firmer statement of the differences between these two drugs (Braun ,
Shul gin & Braun 1980a).

tests sho wed respon ses within norm al limit s. Th e usual

corre la tive side effec ts of ny stagm us, bru xi sm and
anorexia were occasionally noted .
A rem ark abl e co llec tion of anec do ta l report s of
MDM A use has recentl y appeared, descr ibing more than
20 person al experie nces . These first-hand acco unts will
be of keen interest to students of psych ology (Adamso n
1985).
Th e pharm acolog ical and psych opharm acolog ical
findings related to MDMA have been summarized in
se veral review s (Nicho ls & G lenno n 1984 ; Glenn on ,
Rosencran s & You ng 1983; Stafford 1983; Weil & Rosen
1983; Shulgi n 1982 , 1981 , 1978) . Most of these summaries were writte n by the author s of the or igina l scie ntific
studies and there are addi tional data incl uded in these
review s.

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Clinical Studies
The most co mplete publi cati on of the clinical application of MDMA in therapy appeared in 1983 (Greer
1983). It de scribed the results of the administration of
MDMA to 29 patient s in a therapeutic se tting. It concluded that the best use of MDMA is as an adjunct to
insight-o riented psych oth erapy to facilitate co mmunication and intimacy between peopl e involved in em otional
relation ships as well as in the treatm ent of alc oh ol and
other dru g abu se . It was emphas ized that MDMA does not
lend itself to overu se , because its most de sirable effects
diminish with frequ ency of use .
A study invol ving 13 experimental subjec ts was conducted in March 1985 (Greer 1985 b) with the overseeing
of an equa l number of psychi atrists or psychoth erapi sts ,
mos t of who m we re ex per ience d with both MDMA and
LSD actio ns in humans . An exten sive subjective analysi s
was made to develop a co mpa riso n betw een MDMA and
LSD as po tentia l ther apeuti c adj uncts . Th e pr inciple
effe cts of MD MA lasted three to five hou rs , while those of
LSD are known to extend up to 14 hou rs. The clin icians
agreed that M DMA wa s much ea sie r to use than LSD , and
because MDMA did not threaten ego co ntrol , involv ing
little psychological risk to a naive subjec t. Whil e LSD
subjects sometimes ex perience tran sien t delu sion al states ,
the only co mplica tions of using MDM A, acco rdi ng to the
clinicians and researchers, are occasional anxie ty and
vario us physical symptoms due to the sympa tho mimetic
effec ts of the dru g. A descript ion of the clinical protocol
employe d in MDMA therapy has been wr itte n and submitted as a chapter in a forthcoming book (T olbert & Gre er ,
In press).
More qu antitati ve values for these stimulant side
effects were obta ined in a similar study co nducted earlier
on 2 1 subjects (Dow ning & Wo lfso n 1985). Here the
subjec ts were co ntinuo usly monitored for cardio vasc ular
cha nges, neu rological se nsitivity and blood che mis try .
Noteworth y was a relati vely large rise in both systolic and
diastolic pressure at the first hour follo wed by a gradua l
decre ase to below basel ine level by the sixth hour. At
24-hour follow- up , bo th sig ns were still so mewhat depressed . Pul se rate also ro se over the first hour and recov ered during the next five hours. At no point did it dro p
below baselin e during the next 24 hours. All neurol ogical
Journ al o( Psychoactive Drugs

LEGAL HISTORY
Th e initial proposal for the scheduling of MDMA
appea red on July 27 , 1984 (Mulle n 1984a). Here wa s
present ed the usual body of ju sti fication s for the sc heduling of an abu sed dru g , and there was the pro f orma requ est
made for co mments , with non e expected. Co mme nts
were indeed made , however , and a second entry appea red
on December 3 1, 1984 , notin g that hearings we re to be
held (Mullen 1984b ). The date of Febru ary I , 1985, was
set as a tim e to hold a hearin g to establish procedures ,
dates and location s. Th ese hearings were held in 1985 in
Los Angeles , Kan sas Cit y , Missouri, and Wash ington ,
D .C. , and we re presided ove r by an adminis trative law
judge , Francis L. Yo ung .
A requ est appea red in March 1985 for any and all
informat ion co nce rni ng ill icit trafficking an d medi cal
problems assoc iated with MDMA use (Uns igned 1985a).
Thi s was followed, at the end of Ma y 1985, by a not ice
that appear ed in the Fe de ral Register (Lawn 19 85 )
announcing the temporary placem ent of MDMA into
Schedul e I by the invoc atio n of the eme rge ncy scheduling
powers granted by the Comprehensive Crime Co ntrol Act
of 1984 . Th e effecti ve date for this sc heduling was Jul y I ,
1985. Th is occ urred in the middl e of the hearin gs that
were designed to determine the legal fate of MDMA as to
its potential scheduling .
In an administrative development initiall y indep en dent from the sc heduling procedures initiated by the DEA
in 1984, there was a request made throu gh the Food and
Dru g Administration (Ra ndo lph 1984 ) for comments co ncerning the med ical usefulness and abuse poten tial of
some 28 drugs that were being co nsidered by the World
Health Or gani zation for interna tiona l restr iction. MDMA
was explicitly included on this list.

300

Vol. I K(4 ) Oct-D ec II) K6

CH EMISTRY

SHULGIN

recogni zing the values of psychopharmacological agent s

in any of several medical problem areas that are without
good current therap y. Dobl in (1984), who personally
served as a princ iple informati on distribution center during the earliest day s ofthe MDMA co ntroversy, published
the widely circulated book Murm ers in the Heart of the
Beast that made available legal and technical corre spondence. Smith, Wesson and Buffum ( 1985) addressed the
chilling effect of legal scheduling on medical research ,
but were reminded in rebuttal (Holsten & Schie ser 1985)
that the exploratory use of new drug s outside of the
controls that apply to the pharmaceutical industry carry
real risks as to the safety and quality of the product.
Nichols ( 1985) submitted an essay to participants at the
DEA hearings arguing that , according to the published
literature , MDMA should not be considered either a hallu cinogenic agent or an amphetaminelike stimulant.
A perspective article (Riedlinger 1985) reviewed the
recent history of MDMA and speculated on a number of
areas of potential value. Grin spoon and Bakalar ( 1986a)
presented an argument to the medical community supporting the need of drugs as adjun cts to psychotherapy, as well
as having editorialized (Grinspoon & Bakalar 1986b) on
the relationship between designer drugs and the law, using
MDMA as an illustration . The broader question touch ing
on the need of an acknowl edgment of the value of con sciousness alteration in society (using MDMA as a point
of departure) has been presented to the lay community
(Roberts 1986b). Several informational articles or tracts
have appeared that seem reasonabl y neutr al, but emphasize clinical utility nonetheless; they are apparently intended to simply provide information (Greer 1985a; Greer
& Strassman 1985; Grin spoon & Bakalar 1985).
On the let's-discourage-drug-use-and-abuse side,
there have been some noteworthy examples. A short review article in the American Psychological Association' s
APA Monitor (Turkington 1986) quotes statements (see
below) ascribed to the authors of the rat serotonin studies .
Another exa mple is a newsletter on drug abuse (Cohen
1985) that equated all claim s for MDMA to those that
gave LSD and other psychedelics such glowing press
years ago . It is stated that any attempts to set MDMA apart
from MDA, DOM or PMA (or from the user-atte stment
record , from LSD or opium) reflects a lack of knowledge
about these drugs . Furthermore , it indicated that MDM A
appears to be less safe than LSD , and eve n LSD was a
failure.
In addition, some organizations and federal age ncies
have produced tracts and flyers that are directed to the
potential MDMA user, but have been written without
much factual accuracy. Two exa mples are Do It Now
Founda tio n's MDA /MDM (Dye 1982 ), and NID A ' s

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POPULAR OPINIONS
An unusually large amount of commentary and opinion has appeared in the popular press and in both professional as well as lay journals. Occasionally there may be
some statements of fact , but usually there is much misstatement of fact.
The popular press has shown a blend of curio sity and
sensationalism. There were sounds and shades of the LSD
notoriet y of the 1960' s in that each reporter obtained some
facts, but also borrowed detail s from other writers. The
results were an oft-repeated story, generally moderately
accurat e and somewhat favorable . An issue of Brain Mind Bulletin (April 15, 1985) was devoted to the controversy, and a short critical review appeared in the
PharmCh em Newsletter (Seymour 1985). In addition, the
author of the present article has written a hypothetical
question-and-answer interview (Shulgin 1985).
Articles or comm entary also appeared in magazines
and newspapers, such as Daily Californian (Marks 1986),
High Times (Smith & Seymour 1986), New Age (Abramson 1985), Newsweek (Adler 1985), Chemical and Engineering News (Baum 1985), San Francisco Chronicle
(Butler 1985), Oakland Tribun e (Dentinger 1985), Life
(Dowling 1985), San Francisco Examin er (Flinn 1985),
Boston Globe (Foreman 1985 ), Alcoholism & Addiction
(Gold 1985), Vanguard Press (Hudso n 1985; Stevens
1985), Dallas Times Herald (Jube ra 1985), New York
Magazine (Klein 1985), Washington Post (Leavy 1985),
Rolling Stone (O' Rourke 1985), Business Week (Schulman 1985), Psychology Today (Shafe r 1985), Omni
(Siegel 1985), Oklahoma Gazette (Siens 1985), Detroit
News (Tess ler 1985), Time (To ufexis 1985), Scientific
American (Unsigned 1985b), San Francisco Bay Guardian (Wolfson 1985), The Rocket (Eichhorn 1984) and
Substance Abuse Report (Unsigned 1984a). It even made
the comics page , in Doonesbury (Trudea u 1985), and the
editorials on KCBS Radio (Barnett 1985). Two long
essays (Beck 1986; Ehrlich 1986) and a complete book
(Seymour 1986) have appeared coverin g the subject.
One of the first promotional hypes for MDM A
appeared in an underground magazine titled Wet (Unsigned 1981), in which the name Ecstasy was used and
availability was implied as early as 1976 . Another irresponsible tract appeared (Unsigned 1984b) that was styled
to disarm and discourage the potent ial user of MDMA .
This is an exce llent exa mple of inaccur ate and misleading
information where much detail that applies to MDA is
ascribed to MDMA .
In a more balanced vein, a number of reviews and
evaluations acknowledge the abuse potential of MDMA ,
but emphasize the clinical virtue and highlight the need of
Jill/mal

11"Psvc hoact ive Drug

30 1

Vo l. I X(4 j Oct -De c. 19X6

SIWLGI N

CH EMI STRY

"MDMA " (NIDA 1985), a government bulletin warning

of potential psychotic episodes (wherein most informa tion has been taken from the MDA record).

above: " Repeated use of designer drugs such as Ecsta sy

produce s potentially irreversible brain damage. " And an
embarrassing elaboration of this misinformation was
given in a newspaper interview, in which the following is
a verbatim quotation from Dr. Charles Schuster (Associated Press 1986) : "It can poison the nervou s system
probably irreversibly . It may very well be that a young,
healthy adult who is exposed to these drugs is not going to
show frank symptoms that are going to be picked up by a
clinician . But what we don't know is whether 20 or 30
years from now , at the age of 45 , they may begin to be
showing central nervou s system degenerative signs that
ordinaril y would not be seen until they get to be 70 or 80 ."
It further quotes that this is the first demonstration of a
neurotran smitter being modified to a neurotoxin. And
from the NIDA bulletin: " MDMA-Ieads to psychotic
episodes ." All this is an equally inaccurate negative picture, without positive s.

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CONCLUSION
One of the inescapabl e facts of life is that with
MDMA , as with everything that combines both promise
and threat. there arc intense protagonists and intense
antagonists. And both groups are voca l.
From the promotional flyer (Dye 1982) mentioned
above: " When people feel well, centered, unthreatened
and aware of their own strength and loveliness , they are
able to drop many of the usual barriers. Habitual users of
tobacco have no need to smoke. Chain smokers of marijuan a do not need their weed . Nail biters leave their
fingers alone . Compulsive talkers become quiet ," and on
and on: pretty much a glowing picture , without negativ es.
And the opposite extrem e is ju st as unrelenting .
From the APA Monitor (Turkington 1986) mentioned

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